Sumoylation of the progesterone receptor and of the steroid receptor coactivator SRC-1
Sumoylation of the progesterone receptor and of the steroid receptor coactivator SRC-1
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DOI：
10.1074/jbc.m207148200
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发表时间：
2003-04-04
影响因子：
4.8
通讯作者：
Milgrom, E
中科院分区：
文献类型：
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作者：
Chauchereau, A;Amazit, L;Milgrom, E
SUMO-1（小泛素样修饰物）缀合调节多种蛋白质的亚细胞定位、稳定性和活性。我们发现SUMO-1过表达显著增强孕激素受体（PR）介导的基因转录。PR在位于其N-末端结构域的赖氨酸388处经历类小泛素化。然而，受体的SUMO化并不负责增强转录，因为其靶赖氨酸的取代并没有消除SUMO-1的作用，甚至将受体转化为稍微更活跃的反式激活因子。此外，SUMO-1过表达也增强了雌激素受体α（ER α）驱动的转录，与此受体的SUMO化的缺乏形成对比。因此，我们分析了SUMO-1与类固醇受体共激活剂SRC-1的缀合。我们发现，这种蛋白质含有两个主要的位点在赖氨酸-732和赖氨酸-774的共轭。SUMO化显示增加PR-SRC-1相互作用并延长SRC-1在细胞核中的保留。它不能阻止SRC-1泛素化，也不能对蛋白质的稳定性产生明显的影响。SUMO-1的过表达增强PR介导的基因转录，即使在SRC-1的非sumoylated突变体的存在下。这一观察结果表明，在参与类固醇激素介导的基因调控的许多蛋白质伴侣中，有几个可能是SUMO-1修饰的靶点。
SUMO-1 (small ubiquitin-like modifier) conjugation regulates the subcellular localization, stability, and activity of a variety of proteins. We show here that SUMO-1 overexpression markedly enhances progesterone receptor (PR)-mediated gene transcription. PR undergoes a sumoylation at lysine 388 located in its N-terminal domain. However, sumoylation of the receptor is not responsible for enhanced transcription because substitution of its target lysine did not abolish the effect of SUMO-1 and even converted the receptor into a slightly more active transactivator. Furthermore estrogen receptor alpha (ERalpha)-driven transcription is also enhanced by SUMO-1 overexpression contrasting with the absence of sumoylation of this receptor. We thus analyzed SUMO-1 conjugation to the steroid receptor coactivator SRC-1. We showed that this protein contains two major sites of conjugation at Lys-732 and Lys-774. Sumoylation was shown to increase PR-SRC-1 interaction and to prolong SRC-1 retention in the nucleus. It did not prevent SRC-1 ubiquitinylation and did not exert a clear effect on the stability of the protein. Overexpression of SUMO-1 enhanced PR-mediated gene transcription even in the presence of non-sumoylated mutants of SRC-1. This observation suggests that among the many protein partners involved in steroid hormone-mediated gene regulation several are probably targets of SUMO-1 modification.